CZ326499A3 - Composition usable in eye surgery - Google Patents

Abstract

The present invention relates to compositions that maintain structural integrity the anterior chamber of the eye during ophthalmic surgery, thereby protecting the tissues, which form and connect the anterior chamber segment to the possible damage while providing a lasting supply of miotic, a mydriatic or anesthetic agent.

Description

The invention relates to compositions that maintain the structural integrity of the anterior chamber of the eye during ocular surgery, thereby protecting the tissues that form and connect the anterior chamber segment from possible damage while providing a sustained delivery of a miotic, mydriatic or anesthetic agent.

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The controlled-release process releases pharmaceutical substances in the chamber-chamber.

Technical field

The invention relates to compositions comprising a viscoelastic polymer and a miotic or mydriatic agent that maintain the structural integrity of the anterior chamber of the eye during ocular surgery, thereby protecting the tissues that form and join the anterior chamber segment from possible damage while providing sustained delivery of the miotic or mydriatic agent. The invention also provides compositions wherein sustained release of the miotic or mydriatic agent is mediated by microcapsules or copolymer micelles. The invention further relates to compositions comprising a viscoelastic polymer complex and an anesthetic which maintain the structural integrity of the anterior chamber and at the same time consistently deliver an uninfiltrated anesthetic.

BACKGROUND OF THE INVENTION

Maintaining the integrity of the anatomical components of the eye is facilitated by manipulations, in eye surgery, performed on small areas that require concentration and caution.

One component that must be checked is the anterior chamber of the eye. As shown in Figure 1, the anterior chamber is located between the cornea and the iris. Directly behind the iris is a lens that is inserted between the anterior chamber and the larger vitreous chamber, filled with vitreous humor. Maintaining structural integrity of the anterior chamber minimizes the risk of damage to the endothelium and / or iris during surgery

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procedure. The introduction of viscoelastic materials, such as sodium hyaluronate, chondroitin sulfate, hydroxypropylmethylcellulose and methylcellulose, into the anterior chamber prevents the chamber from collapsing during surgery.

Another component that should be checked is the doll size. During cataract surgery, it is desirable that the doll be expanded to facilitate access to the lens and facilitate insertion of the posterior chamber implant. A number of mydriatic active ingredients are used for this purpose, such as atropine (a cholinergic blocking agent), phenylephrine (an adrenergic stimulator), and prostaglandin inhibitors, which are mainly administered by external administration.

On the other hand, in the implantation of rebound implants and secondary aphakic implants, it is desirable to reduce (using miotic agents) the doll, which will reduce iris damage, eliminate corneal irritation, prevent ocular muscle shirring, and facilitate implant placement. For this purpose externally applied pilocarpine and carbachol (cholinergic stimulators) and physostigmine, demecarium bromide, echothiophate iodide and isofluorphate (cholinesterase inhibitors) are used.

However, during surgery and when the eye is opened, the effectiveness of topical medication decreases. Dilution and leaching prevent long-term exposure to high doses of active substance. The direct introduction of miotic agents such as acetylcholine chloride or carbachol does not provide long-term effects and often requires frequent and repeated application of the active agent to the open eye.

Previous attempts to achieve a sustained level of active substance in the long term used permanent transport technology.

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• the active ingredient by systemic or transdermal administration, or by placing a biologically eroding device to deliver the active ingredient outside the eye. These methods have been used primarily to control intraocular pressure in patients with glaucoma. However, to date, a method has not been proposed that combines the sustained delivery of a mydriatic or miotic active ingredient together with maintaining the structural integrity of the anterior chamber.

Local anesthesia is the mainstay of eye surgery. Topical agents are used for corneal and conjunctival anesthesia and infiltration anesthetics are used to create sensory anesthesia and motor acinesis that are necessary for ophthalmic surgery. When injected into a muscle cone, these agents anesthetize the cellular ganglion, afferent nerves, and motor innervation to extraocular muscles. However, retrobulbar haemorrhage caused by muscular or vascular trauma is a potential complication of this form of anesthesia, which may prevent surgery itself. In uncommon cases, perforation of the eye ball, damage to the optic nerve and even loss of vision can occur. In addition, systemic absorption of the anesthetic can cause seizures, respiratory problems and even death.

In order to avoid these potential complications, infiltration anesthesia is performed by sub-tendon and sub-conjunctival injections and by direct infiltration of one or more extraocular muscles. This approach, while somewhat awkward and uncomfortable, reduces the potential complications associated with anesthesia, but, on the other hand, entails risks such as chemosis, sub-conjunctival or subcutaneous bleeding and incomplete sensory and

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4 • ·

motor anesthesia, especially during handling of the body and iris.

Along with the development of extracapsular cataract surgery, a different set of anesthesia requirements has been derived. The need for motor anesthesia was reduced as soon as appropriate instrumentation could be used to fix the eye ball during surgery. The need for frost sutures, the application of which may be painful, has been substantially eliminated. The remaining requirement is the requirement to exclude the perception of pain, especially pain caused by iris manipulation. In this context, intracameral anesthetics are used and are applied directly to the anterior chamber.

The use of an intracameral anesthetic may be effective, but may require frequent instillation of the anesthetic, especially if the procedure requires additional steps and the surgeon is unable to safely add additional material. In addition, conventional anesthetic solutions typically leave the eye rapidly through surgical incision, normal discharge channels, and the surface of the iris and ciliary body.

In this regard, it would be desirable to have a system that maintains the presence of the anesthetic and at the same time reduces the performance of intracameral placement and immediate loss of the anesthetic through the aforementioned routes. Further, it would be desirable to provide a drug delivery system that releases the anesthetic uniformly over time and that controls the osmotic pressure associated with establishing an equilibrium state between anesthetic ions and ions existing in ocular fluids.

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• · ►

SUMMARY OF THE INVENTION

The invention relates to compositions which can be used to maintain the structural integrity of the anterior chamber and to provide sustained release of the miotic, mydriatic and / or anesthetic active ingredient. In various embodiments of the invention, the compositions of the invention comprise a viscoelastic polymer, wherein sustained release of the miotic, mydriatic and / or anesthetic active agent is mediated by ionic interactions. In other embodiments of the invention, the sustained release of the miotic, mydriatic and / or anesthetic active ingredient is mediated by microcapsules or copolymer micelles. In certain embodiments, the compositions of the invention can be used for both rapid release of a miotic, mydriatic and / or anesthetic active agent, and slow release, both being sustained release.

Brief description of the pictures

Giant. 1 shows Figure 501 of the element "Anatomy, 1978, Lea and Fibiger, Philadelphia;

Giant. 2 shows the dilution effect of miotic or mydriatic active agents in the anterior chamber of the eye caused by normal aqueous humor exchange in the presence or absence of a viscoelastic polymer / drug complex; curve A represents unbound drug substance = 0.0500 mol / l in physiological saline; curve B represents unbound drug substance = 0.025 mol / l + viscoelastic polymer complex and drug substance = 0.0500 equiv / L in physiological saline; and curve C represents the viscoelastic polymer complex a

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active ingredient = 0.100 equiv / L in physiological saline;

Giant. 3 shows the attenuating effect of the anesthetic agent lidocaine in the anterior chamber, caused by the normal degree of aqueous humor conversion in the presence or absence of anesthetic and viscoelastic polymer complexes: curve A represents unbound anesthetic = 0.0085 mol / L in physiological saline; curve B represents unbound anesthetic = 0.0049 mol / L + anesthetic-viscoelastic polymer complex = 0.150 equiv / L in physiological saline; and curve C represents an anesthetic-viscoelastic polymer complex = 0.348 equiv / L in physiological saline.

For the sake of clarity, the detailed description of the invention is divided into the following sections:

(1) viscoelastic polymers;

(2) miotic agents;

(3) mydriatic agents;

(4) anesthetic agents;

(5) compositions of the invention; and (6) methods of using the compositions of the invention.

(1) Viscoelastic polymers

The invention provides compositions comprising viscoelastic polymers, including but not limited to anionic viscoelastic polymers, such as hyaluronic acid (hyaluronate), chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxypropyl cellulose, carboxymethylhydroxypropyl cellulose, cellulose,

01-2059-99-English • carboxymethylguar, carboxymethylhydroxypropylguar, carboxymethylhydroxyethylguar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, alginates, furcellarone, pectins, gum arabic, tragacanth, starch, carragen, carragen starch, glycoaminoglycans, polysaccharides, polypeptides, anionic polysaccharides, anionic proteins and polypeptides, anionic polyacrylamides, anionic poly-N-vinylpyrrolidones, anionic polydimethylacrylamide, polymers and copolymers of acrylamide acid, methacrylamide acid, dimethyrylic acid, Nv. 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid and 2-methacryloyloxyethylsulfonic acid. The aforementioned compounds can act as acid polymers in their unionized free acid form and as polymeric anions in their ionized form.

acrylic, maleic,

The viscoelastic polymers of the invention have a molecular weight of 50,000 to 8,000,000 daltons, depending on the particular polymer selected from commercially available polymers that have been approved for use in ophthalmology. For example, an average molecular weight of 1,000,000 to 5,000,000 daltons is typically used for sodium hyaluronate, while an average molecular weight of more than 80,000 daltons is typically used for hydroxypropylmethylcellulose. For sodium hyaluronate, a molecular weight of 5,000,000 daltons is commonly used in ophthalmic surgery. The viscoelastic polymer concentration can range from 1 mg / ml to 60 mg / ml and preferably from 5 mg / ml to 30 mg / ml. The viscosity of the viscoelastic polymer may be in the range of

000 centistokes to 60 000 centistokes and preferably from

500 centistokes to 5 500 centistokes for hydroxy01-2059-99-Ce propyl methylcellulose and from 20 000 centistokes to 40 000 centistokes for sodium hyaluronate. These viscosities not only allow the polymer to be introduced into the eye by injection or extrusion, but are also viscous enough to remain within the anterior chamber (i.e., do not easily flush), maintain its structural integrity and allow it to be easily aspirated. In addition, the viscoelastic polymers of the invention are water-soluble and can be eluted over time.

(2) Miotic agents

The invention provides compositions comprising miotic agents, including, but not limited to, pilocarpine, isopilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, isopilocarpine hydrochloride, isopilocarpine nitrate, carbachol, physostigmine, physostigmine sulfate, physostigmine sulfide, demecarium bromide, ecothiocide bromide and acetylcholine chloride. Preferred agents are members of the pilocarpine and isopilocarpine family of compounds.

The miotic agents of the invention may be used in either neutral or charged cationic form, depending on the nature of the sustained delivery of the active ingredient for which the composition is intended. Pilocarpine, isopilocarpine and physostigmine may be considered as the basic agent; also hydrophobic agents include pilocarpine, isopilocarpine and physostigmine; and cationic agents include demecarium bromide, ecothiophate iodide, pilocarpine hydrochloride, pilocarpine nitrate, isopilocarpine hydrochloride, isopilocarpine nitrate, carbachol, physostigmine sulfate, acetylcholine chloride and physostigmine sulphide.

01-2059-99-English • 4 4 44 · 4 4 4 (3) Mydriatic agents

The invention provides compositions comprising mydriatic agents, including but not limited to, atropine, atropine sulfate, atropine hydrochloride, atropine methyl bromide, atropine methyl nitrate, hyperduric atropine, atropine N-oxide, phenylephrine, phenylephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, -hydrochloride, hydroxyamphetamine iodide, cyclopentolate, cyclopentolate hydrochloride, homatropine, homatropine hydrobromide, homatropine hydrochloride, homatropine methyl bromide, scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, tropopridine amide, scopolaminomethylbromide, scopolaminomethylbromide, scopolamine sorbide hydrobromide and tropicamide hydrochloride. Preferred agents are members of the atropine family and the phenylephrine family of compounds.

The mydriatic agents of the invention may be used either in neutral or charged cationic form, depending on the nature of the sustained delivery of the active ingredient for which the composition is intended. From the above list, the basic agents include atropine, phenylephrine, hydroxyamphetamine, cyclopentolate, homatropin, scopolamine and tropicamide; hydrophobic agents include atropine, phenylephrine, hydroxyamphetamine, cyclopentolate, homatropin, scopolamine, and tropicamide; and cationic agents include atropine sulfate, atropine hydrochloride, atropine methyl bromide, atropine methyl nitrate, hyperduric atropine, atropine N-oxide, phenylephrine hydrochloride, hydroxyamphetamine iodide, hydroxyamphetamine hydrobromide, cyclopentolate hydrochloride, homatropin hydrochloride, homatropine homatropin methyl bromide, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine methyl bromide, scopolamine01-2059-99-Ce • · ·· ·· * ··. , Aa aa aa aa aa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa methyl nitrate, scopolamine N-oxide, tropicamide and tropicamide hydrobromide.

(4) anesthetic agents methocaine, tetracaine, butoxycaine,

The invention provides compositions comprising anesthetic agents with a positive charge (cationic ammonium salts) or a potential positive charge (non-charged amino groups) such as agents including lidocaine, proparacaine, tetracaine, phenacaine, naepain, cocaine, bethoxycaine, bupivacaine, butacaine, butanilicaine, butoxycaine, cartaicaine, cyclomethycaine, dibucaine, diformcaine, hexylcaine, hydroxymepivacaine, meprylcaine, metaoctacaine, orthocaine, oxethazine, pipetocaine, pyridocaine, pyridocaine, pfilocaine, prococaine, propaocaine, propaocaine, propaocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine, trimekain. Preferred agents are lidocaine, proparacaine and tetracaine.

etidocaine, leucinocaine, myrtecaine,

The anesthetic agents of the invention may be used in their neutral, uncharged form or in their cationic charged form, the choice of use depending on the sustained mode of drug delivery that the composition is intended to provide. All neutral compounds of the above list contain primary amino groups, secondary amino groups and / or tertiary amino groups, while the charged cationic groups include the hydrochloride salts, nitrate salts, sulfate salts, mesylate salts, butyrate salts, acetate salts, tartrate salts, citrate salts or phosphate salts thereof. amino acids which are obtained by protonation of the primary, secondary or tertiary amino group with the appropriate acids. Neutral aminoanesthetic agents činidlaφ φ φφφ · ·

01-2059-99-What are lidocaine, tetracaine, proparacaine, naepain, cocaine, phenacaine, bethoxycaine, bupivacaine, butacaine, butanilicaine, butoxycaine, butoxycaine, butoxycaine etidocaine, tetracaine, leucinocaine, cyclomethycaine, dibucaine, diformocaine, hexylcaine, hydroxymepivacaine, meprylcaine, metabutoxycaine, myrtekaine, octacaine, orthocaine, oxethazine, parethoxykaine, piperokaine, properokaine, propidokaine, procaocaine, procaocaine, procaocaine, tolylcaine, tricaine and trimecaine. Charged cationic anesthetic agents are prepared from the above-described agents by protonation with acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methylsulfonic acid, butyric acid, acetic acid, citric acid and tartaric acid.

(5) The composition of the invention

The invention provides compositions that allow sustained release of the above-described miotic, mydriatic and / or anesthetic agents, and wherein the release of the agent is mediated by (1) ionic (including acid-base) interactions; (2) microcapsules; or (3) copolymer micelles. The compositions of the invention also provide a means for maintaining structural integrity of the anterior chamber.

In a first set of non-limiting embodiments, the invention provides compositions in which sustained release of a miotic or mydriatic agent is achieved through ionic interactions between the agent and the viscoelastic polymer. In certain embodiments, the composition may comprise an anionic viscoelastic polymer and a cationic miotic or mydriatic agent which, when the composition is

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of the invention applied to the eye, it can be released by displacement by endogenous sodium or potassium ions or other naturally occurring cations. In a particular non-limiting embodiment, the anionic viscoelastic polymeric acid may be sodium hyaluronate and the cationic agent may be mydriatic agent atropine sulfate, wherein in preparing the composition sodium sulfate (and hydrogen sulfate) is removed using an excess of atropine sulfate in the presence of less sodium hyaluronate and subsequent dialysis. High purity atropine hyaluronate can be prepared by repeating this process several times. In another specific non-limiting embodiment, the anionic viscoelastic polymer may be chondroitin sulfate and the cationic agent may be a miotic agent pilocarpine obtainable by reacting sodium chondroitin sulfate with pilocarpine hydrochloride. In yet another specific non-limiting embodiment, an ion exchange interaction between sodium hyaluronate and phenylephrine hydrochloride can provide phenyephrine hyaluronate.

In a second derived set of non-limiting embodiments, the invention provides compositions in which sustained release of a miotic or mydriatic agent is achieved by ionic acid-base interactions between the agent and the viscoelastic polymer. In certain embodiments, the composition of the invention may comprise an acidic viscoelastic polymer and a basic miotic or mydriatic agent. In this case, when placed in an eye environment of approximately neutral pH, the composition will allow relatively slow release of the miotic or mydriatic agent by ionic displacement of the active agent from existing cations. In one particular non-limiting embodiment, the acidic viscoelastic polymeric acid may be hyaluronic acid and the basic agent may be

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Mydriatic agent atropine. When the two compounds are combined in the composition, the polymer salt of atropinhyaluronate may be formed. In another specific non-limiting embodiment, hyaluronic acid can interact with the basic miotic active ingredient, pilocarpine, in water at 5-50 ° C (pilocarpine is protonated with polymeric acid and converted to a viscoelastic polymer salt), wherein subsequent dialysis or ultrafiltration removes unreacted pilocarpine. The resulting pilocarpine hyaluronate-based composition can then be sterilized and its pH and osmolality adjusted (e.g., the pH may range from about 6.8 to 7.8, preferably from 7.2 to 7, 4 and the osmolality value is 285 ± 55 mOsm / kg, and preferably ranges from 290 to 320 mOsm / kg) or may be isolated by vacuum drying or lyophilization. In yet another particular non-limiting embodiment of the invention, hyaluronic acid may be reacted with a mydriatic agent, phenylephrine, in aqueous solution using phenylephrine in excess to form phenylephrine hyaluronate, wherein the remaining phenylephrine is removed from the product by dialysis.

Giant. 2 shows three representative examples of sustained release of a miotic or mydriatic agent from the anterior chamber of the eye under the following conditions. The aqueous volume of the aqueous humor is 310 μΐ and the aqueous water exchange rate of 1.5 μΐ / min (Schoenwald, 1993, “Pharmacokinetics in Ocular Drug Delivery (Chapter 10) in Biopharmaceuticals of Ocular Drug Delivery, CRC Press, Inc., Boča Raton, Fl. ). Unbound drug values are reported in moles per liter, and viscoelastic polymers are reported as equivalents per liter. These values describe any •

I «• ·

Complex of viscoelastic polymer and any miotic or mydriatic active ingredient.

The curve A in FIG. 2 represents the unbound active substance, whose concentration decreased from an initial concentration of 0.0500 mol / l to 0.0084 mol / l as a result of the aqueous humor change after six hours in the eye.

bound polymer.

The curve B in FIG. 2 represents a combination of unbound drug (lack viscoelastic polymer) and ionically complexed drug-viscoelastic This curve has a predicted relative binding constant of the interaction of 5 x 10 ² (Hayakawa et al., 1983, Macromolecules 16: 1642). This value was determined for carboxymethylcellulose (as an anionic viscoelastic polymer model) and hydrophilic dodecyltrimethylammonium ion cation. It can be seen from curve B that the initial concentration of unbound active substance decreased to 0.0340 mol / l after six hours due to the replacement of aqueous humor in the anterior chamber. This final concentration is more than four times higher than the concentration of unbound drug after six hours of observation.

The curve C in FIG. 2 represents an ion-bound complex of active substance and a viscoelastic polymer in which an initial concentration of 0.100 equiv./l (producing an equilibrium initial concentration of 0.500 mol / l unbound active substance) is reduced to 0.0354 after six hours of presence in the eye mol / 1. This final concentration is more than four times higher than the final concentration of unbound active substance and even slightly higher than that of curve B. On this curve, the viscoelastic polymer-active compound complex is predicted

01-2059-99-Ce 5 x 10 ^-2 co-interaction constant (Hayakawa et al., 1983, Macromolecules 16: 1642).

Thus, from FIG. 2 shows that two examples of the ion-bound complex of the miotic or mydriatic active agent and the polymer clearly demonstrate the effects of sustained release of the active agent in the anterior chamber of the eye as compared to the unbound active agent.

In a third set of non-limiting embodiments, the invention provides compositions comprising microcapsules that are soluble or have the ability to swell in an aqueous environment and which are preferably biodegradable. These microcapsules contain a miotic or mydriatic agent which can be washed away over time as the microcapsule slowly dissolves, disintegrates or swells. As a rule, it is desirable that these microcapsules be smaller than the wavelength of light and so do not cause light scattering and poor vision. In this process, the selected agent is incorporated into the microcapsule during manufacture of the microcapsule. Since the viscosity of the microcapsules is generally low, they need to be supplemented with a viscoelastic polymer to retain the anterior chamber of the eye.

Soluble microcapsules can be derived from inherently biodegradable polymers such as poly-DLlactide or DL-lactide-glycolide copolymers, which can be incorporated in dry form into microcapsules containing the appropriate agent (Clarke et al., 1994, Polymer Preprints 35 (2): 73). Alternatively, the microcapsules can be derived from pH-sensitive polymers in which a change in pH causes the microcapsule to expand resulting in sustained release of the active ingredient. An example of such pH-sensitive polymers is (L) -lysine-alt-terephthalic acid, which at pH

• · · · ·· · ·· ·· • ··· · · · · 01-2059-99-Ce • · · • · · · · · · · • · · · · · • · · · · · · · • · · · · · ·· · · · · · · · 16 values higher than 6 expands (Makino et al., 1994, Polymer Preprints, 35: 54). Biological degradable

microcapsules containing a miotic or mydriatic agent can be prepared using a polymer, for example polylactide or lactide-glycolide copolymers, which decompose over time.

In a fourth set of non-limiting embodiments, the invention provides compositions comprising soluble copolymer micelles comprising a hydrophilic and hydrophobic portion, and the agent (in its unchanged form) is absorbed in the hydrophobic portion of the copolymer micelle (Area et al., 1994, Polymer Preprints 35: 71). At equilibrium, it is expected that the hydrophobic active ingredient, for example phenylephrine, will rest both inside and outside the copolymer micelle. Once placed in the anterior chamber of the eye to remove the external agent, the internal agent may be released slowly. These copolymer micelles may preferably have a hydrophilic-hydrophobic or hydrophilic-hydrophobic-hydrophilic character. The hydrophilic blocks are preferably derived from ethylene oxide and the hydrophobic blocks are derived from propylene oxide (ethylene oxide-propylene oxide-ethylene oxide block copolymers sold under the trade name Pluronic or Ploxamer). Compositions containing copolymer micelles can be mixed with a viscoelastic polymer, for example, hydroxypropyl methylcellulose, to maintain the structural integrity of the anterior chamber.

The invention further provides compositions comprising a plurality of miotic, mydriatic and / or anesthetic agents and mixtures thereof.

The amount of miotic or mydriatic agent that is present in the composition may be the amount it provides

01-2059-99-English · 4 4

the desired therapeutic effect; ie. the desired doll size for the desired long period of time. These amounts will vary for particular agents, but can be readily determined using a well-known dose-response relationship known to those skilled in the art. The concentration of the miotic or mydriatic agent may range from 0.001 mg / ml to 20 mg / ml and preferably from 0.025 mg / ml to 10 mg / ml. As one specific, non-limiting example, in which the miotic active agent is acetylcholine chloride, the formulation of the polymer / active ingredient complex can be prepared using a solution of acetylcholine chloride and acetylcholine hyaluronate wherein the acetylcholine concentration can be 10 mg / ml and the osmolality can be with mannitol set to 305 mOsm / kg. As another specific non-limiting example in which the miotic agent is pilocarpine hydrochloride, the formulation of a polymer / active ingredient complex can be prepared using a solution of pilocarpine hydrochloride and pilocarpine hyaluronate where the concentration of pilocarpine can be 1 mg / ml and osmolality can be mannitol set to 305 mOsm / kg. As yet another specific non-limiting example in which the mydriatic agent is atropine sulfate, the formulation of the polymer-active complex formulation can be prepared using an atropine hyaluronate and atropine sulfate solution wherein the atropine concentration can be 0.3 mg / ml and the osmolality can be be set to 305 mOsm / kg with mannitol. In each of the foregoing examples of this paragraph, the cationic active ingredient may be mixed with the polymer complex and the active ingredient in sterile water, and the osmolality may subsequently be adjusted using a neutral agent such as mannitol.

The invention provides compositions which allow sustained release of the above-mentioned anesthetic agents, wherein:

01-2059-99-English · · · ·

release of the agent is mediated by ionic interactions between the viscoelastic polymer and the anesthetic active agent. These compositions also provide a means for maintaining structural integrity of the anterior chamber.

In a fifth set of non-limiting embodiments, the invention provides compositions wherein sustained release of the anesthetic agent is achieved through ionic interactions between the anesthetic agent and the viscoelastic polymer. In particular embodiments, the composition may comprise an anionic viscoelastic polymer and a cationic anesthetic agent which, when applied to the eye, may be released by displacement with endogenous sodium or potassium ions or other naturally occurring cations. In a specific non-limiting embodiment, the anionic viscoelastic polymer may be sodium hyaluronate and the cationic agent may be lidocaine hydrochloride. In preparing this composition, sodium chloride is removed by excess lidocaine hydrochloride in the presence of minor amounts of sodium hyaluronate and subsequent dialysis. This process can be repeated several times to prepare a very pure lidocaine hyaluronate ion complex. In another specific non-limiting embodiment, the anionic viscoelastic polymer may be sodium chondroitin sulfate and the cationic agent may be an anesthetic, tetracaine hydrochloride, which may be mixed. This tetracaine-chondroitin sulfate ion complex can be prepared by the interaction of sodium chondroitin sulfate with tetracaine hydrochloride. In yet another specific embodiment, the ion exchange interaction between sodium hylauronate and proparacaine hydrochloride provides a proparacaine hyaluronate ion complex.

• ·

01-2059-99-Ce

In a sixth set of non-limiting embodiments, the invention provides compositions wherein sustained release of anesthetic agents is achieved by ionic acid-base interactions between the agent and the viscoelastic polymer. In these embodiments, the composition may comprise an acidic viscoelastic polymer (in its free acid form) and a basic anesthetic agent (in its neutral aminoform). When placed in the eye, the composition will relatively slowly release the anesthetic agent that will be displaced by the cations present. In a particular non-limiting embodiment, the acidic viscoelastic polymer may be hyaluronic acid and the basic agent may be a neutral anesthetic agent lidocaine. When the two compounds are combined by acid-base interaction in the composition, a polymeric lidocaine hyaluronate complex can be formed. In another specific non-limiting embodiment, hyaluronic acid can be reacted with a basic anesthetic agent, proparacaine, in water at a temperature of 5-50 ° C (in which the proparacaine is protonated with a polyacid and becomes a salt of a viscoelastic polymer) followed by dialysis and filtration or ultrafiltration. removes unreacted lidocaine. The obtained lidocaine hyaluronate composition can then be either sterilized and adjusted to a suitable pH and osmolality for use (for example, a pH of about 6.8 to 7.9, preferably 7.2 to 7.4 and an osmolality of 285 + 55 mOsm / kg and preferably 290-320 mOsm / kg) or may be isolated by vacuum drying or lyophilization. In yet another specific, non-limiting embodiment of the invention, hyaluronic acid can be reacted with an anesthetic agent, proparacaine, in aqueous solution using an excess of proparacaine, followed by filtration and dialysis to form a proparacaine-hyaluronate ionic polymer complex.

• ·

01-2059-99-Ce

Giant. 3 shows a non-limiting example of sustained release of the anesthetic agent, specifically showing three representative conditions of use of a 1.5 μΙ / min aqueous humor conversion rate (Schoenwald 1993, Pharmacokinetics in Ocular Drug Delivery (Chapter 10) in Biopharmaceuticals of Ocular Drug Delivery, CRC Press, Inc). ., Boca Raton FL). Units for unbound anesthetic are given in mol / l and units for viscoelastic polymers are given in equiv./l units, which would describe combinations of any viscoelastic polymer with any anesthetic agent. The total initial concentration of the anesthetic, in this case specifically lidocaine, is 0.0085 mol / l.

Lidocaine has been reported to bind to plasma at a concentration of 1 gg / ml to 4 gg / ml, with 60% to 80% lidocaine bound to the protein (Xylocaine (lidocaine hydrochloride) information leaflet, ASTRA Pharmaceutical Co.). Assuming that this bond between the cationic lidocaine and the anionic groups in the plasma is ionic in nature, the equilibrium constant for binding of lidocaine to the anionic polymer would be 0.433.

The curve A in FIG. 3 represents an unbound anesthetic whose initial concentration of 0.00850 mol / l decreased after six hours of dilution in the anterior chamber (at a total volume of 0.8 ml) due to the conversion of aqueous humor to 0.00143 mol / l. This represents an 83% decrease in lidocaine concentration.

The curve B in FIG. 3 represents a combination of unbound lidocaine (no viscoelastic polymer present) and an ionic (bound) anesthetic and viscoelastic polymer. For this curve, the complex was • 4

01-2059-99-Ce anesthetic and viscoelastic polymer calculated equilibrium constant 0.433. Curve B shows that the initial concentration of unbound anesthetic 0.0490 mol / l and the associated anesthetic 0.150 equiv./l (obtained at an initial unbound lidocaine concentration of 0.00850 mol / l) after six hours of aqueous humor conversion decreased the lidocaine concentration in the front chamber to 0.00512 mol / l. This represents a 40% reduction in lidocaine concentration. However, this final concentration is more than 3.6 times greater than the final concentration of unbound drug after six hours of conversion.

The curve C in FIG. 3 represents an ionic complex of (bound) anesthetic and viscoelastic polymer having an equilibrium constant of 0.433 and shows that the initial concentration of 0.348 equiv./l (obtained at an initial unbound lidocaine concentration of 0.0085 mol / l) decreased as a result of aqueous humor conversion. 6 hours of dilution in the eye to 0.00621 mol / L lidocaine. This final concentration represents the slightest decrease in lidocaine concentration of 27%. This final concentration of lidocaine in the case of the anesthetic-polymer complex is more than 4.3-fold greater than the final unbound anesthetic concentration and approximately 17% greater than the unbound anesthetic concentration in the presence of the anesthetic-polymer complex (curve B).

FIG. Thus, it can be seen that the conditions of curve B and curve C using an anesthetic-viscoelastic polymer ion complex clearly demonstrate the effect of sustained release of the anesthetic in the anterior eye chamber, unlike unbound anesthetic.

01-2059-99-Ce

The invention further provides compositions comprising a plurality of anesthetic agents and / or a plurality of viscoelastic polymers.

The amount of anesthetic agent contained in the composition may be an amount that produces the desired therapeutic effect, i.e., the desired level of anesthesia. These amounts will vary for different agents, but one skilled in the art can readily determine these amounts by dose-response relationships. The concentration of the anesthetic agent may range from 1 mg / ml to 50 mg / ml and preferably from 5 mg / ml to 20 mg / ml. As a specific non-limiting example in which the anesthetic is lidocaine hydrochloride, the anesthetic-polymer complex can be prepared from a solution of lidocaine hydrochloride and lidocaine hyaluronate in which the lidocaine concentration can be 20 mg / ml and the osmolality can be adjusted to 305 mOsm / kg with mannitol. As yet another specific non-limiting example, where the anesthetic agent will be tetracaine hydrochloride, an anesthetic-polymer complex formulation can be prepared using a tetracaine hyaluronate solution containing tetracaine hydrochloride where the tetracaine concentration can range from 5 to 20 mg / ml and the osmolality can be adjusted with mannitol to 305 mOsm / kg. As yet another specific non-limiting example using proparacaine as the anesthetic agent, a proparacaine hyaluronate solution containing proparacaine hydrochloride can be prepared in which the proparacaine concentration can range from 5 to 20 mg / ml and the osmolaite can be adjusted to 305 mOsm / kg by mannitol. In each of the preceding examples in this paragraph, a cationic anesthetic agent in sterilized water can be mixed with a polymer-anesthetic agent complex, and the osmolality can then be adjusted using a neutral agent such as • 4 4 4

01-2059-99-English fr>

4

in this case mannitol. In yet another specific non-limiting example, the anesthetic-polymer complex can be mixed with a solution of another viscoelastic polymer and the osmolality can be adjusted using a neutral agent such as mannitol.

The invention further provides compositions that sustainably release anesthetic agents in combination with miotic or mydriatic agents. In particular, the invention comprises a viscoelastic polymer complex of anesthetic and miotic agent, and a complex of viscoelastic polymer, anesthetic and mydriatic agent, wherein the release of anesthetic agents and active agents is mediated by ionic interactions between the viscoelastic polymer and anesthetic agents and the miotic or mydriatic agent. These compositions also provide a means for maintaining structural integrity of the anterior chamber.

Since it is important to maintain the anterior chamber of the anterior chamber during ophthalmic surgery, the compositions of the invention preferably exhibit an osmolality which, when introduced into the eye, does not adversely affect the anterior chamber of the eye. The osmolality of the natural content of the anterior eye chamber ranges from 301 to 305 mOsm / kg (Geigy Scientific Tables, Vol. 1, ed. C. Lentner, 8th edition, 1981, Basle, Switzerland). The osmolality of the ionic complex of the viscoelastic polymer and the active agent can be maintained by an excess of the active agent in its salt form (for example, a 3.0% phenylephrine chloride solution is isotonic compared to 0.9% by weight NaCl solution). In salt form, it may also be maintained by a solution of a neutral agent such as glycerin (where a 2.6 wt% solution is isotonic compared to a 0.9 wt% NaCl solution) or

01-2059-99-English • 4 44> * 4 <

»4 4 1 ► 4 4 I Mannitol (5.07% isotonic compared to 0.9% NaCl by weight) or in combination with this neutral agent. If traditional isotonic solutions are used, which may contain sodium ions, potassium ions, calcium ions, etc., then these ions may displace the ions bound by the active ingredient and release it into solution, and it may be desirable to add an excess to rebalance the polymer and the active ingredient. cationic active compounds. In preferred embodiments of the invention, the osmolality of the compositions may range from about 280 to 340 mOsm / kg, and preferably from about 280 to 340 mOsm / kg.

In order to maintain the structural integrity of the anterior ocular chamber, the composition of the invention must be sufficiently viscous to prevent the chamber from collapsing during surgery. However, these compositions should also be sufficiently fluid to be introduced into the anterior chamber by injection or extrusion and also to be removed (e.g., by irrigation) at the conclusion of the surgery. Thus, the viscosity of the composition of the invention is in the range of 1,000 to 60,000 centistokes and preferably of 2,500 to 40,000 centistokes. When viscoelastic polymers are used, their concentrations are preferably in the range of about 10 mg / ml to 30 mg / ml in aqueous (preferably isotonic) solution.

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01-2059-99-Ce

(6) Methods of using the composition of the invention

The compositions of the invention are particularly useful when used during ophthalmic surgical procedures, for example those requiring pupil enlargement, such as intracapsular and extracapsular surgical procedures and fistulizing procedures, and procedures requiring doll narrowing, such as operations of anterior chamber of the eye, in particular vitreous surgical separation - corneal adhesion, separation of iris-corneal adhesion and introduction of phakic refractive implants and secondary aphakic implants.

For example, the compositions of the invention containing a mydriatic agent can be used in standard extracapsular ophthalmic surgery performed under topical or retrobulbar anesthesia. It should be noted that retrobulbar anesthesia tends to make the iris somewhat more sensitive to tapering or widening drops (Starling's Law). The mydriatic composition of the invention may then be injected into the anterior chamber of the eye before and / or after the appropriate capsulotomy. Subsequently, irrigation, aspiration, expression or phacoemulsification may be performed. The implant can then be inserted and the remaining mydriatic viscous material flushed out of the eye. In these procedures, the composition of the invention can assist in lens extraction and implant placement.

Non-limitingly, the miotic compositions of the invention may also be used in standard procedures for introducing a myopic refractive implant. After paracentesis, miotic compositions can be injected into the anterior chamber. It can be introduced after making it available

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• A A A A A • A A AND AND A A A A A A AND AND AND AND AA A A AND AND AND AND AND AND • A A A AND AND AND AND AAA • A A A A AAA A A

And, the implant, the wound may be sutured and the viscous miotic composition may be rinsed from the eye.

The use of the compositions of the invention offers a number of advantages. A first advantage of the compositions of the invention is that it can simultaneously provide both mechanical and pharmaceutical activities useful in ophthalmic surgery. A second advantage of the compositions of the invention is that they allow the sustained release of miotic or mydriatic agents during surgery. A third advantage of the compositions of the invention is that they can prevent or limit the increase in intraocular pressure which may be associated with the use of a viscoelastic solution not containing a miotic agent. A fourth advantage of the compositions of the invention is that they can be used to prevent posterior or anterior chamber growth by keeping the dilated pupil in the postoperative phase (the phase immediately after the operation).

In addition, during normal surgery, iris tension is reduced in addition to reducing chamber tension. Since the viscous compositions of the present invention maintain a certain ventricular pressure and, to some extent, the intraocular pressure, and are in contact with the iris for a longer period of time, there is a so-called "reservoir effect and chamber retention" which increases the iris tension. In addition, especially when it is desired to narrow the cornea, the long-acting narrowing may limit the pressure increase caused by the viscoelastic material.

In another non-limiting embodiment, the compositions of the invention comprising a viscoelastic polymer and an anesthetic can be used in particular in cataract and glaucoma surgery and other intraocular processes. For example, topical anesthesia can be used to anesthetize the corneal and conjunctival surfaces. Thereafter, the paracentesis is then performed to allow

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a gradual drainage of the anterior chamber of the eye, which is filled with a complex of viscoelastic polymer and anesthetic through the injection. The chamber is deepened as desired and surgery is initiated.

Claims (36)

PATENT CLAIMS A composition for use in ophthalmic surgery comprising a viscoelastic polymer and an effective amount of an anesthetic agent. The composition of claim 1, wherein the viscoelastic polymer is acidic and the anesthetic agent is basic. 3. The composition of claim 1 wherein the viscoelastic polymer is anionic and the anesthetic agent is cationic. The composition of claim 1, wherein the viscoelastic polymer and the anesthetic agent form a complex of the viscoelastic polymer and the anesthetic agent. 5. A composition useful in ophthalmic surgery comprising a viscoelastic polymer, an anesthetic agent and an active agent, wherein the viscoelastic polymer, anesthetic agent and the active agent form an ionic complex of viscoelastic polymer, anesthetics. The active ingredient is selected from the group consisting of miotic and mydriatic agents. Composition according to claim 5, characterized in that the miotic and mydriatic agents are selected from the group consisting of atropine, pilocarpine, phenylephrine, isopilocarpine, acetylcholine, atropine sulfate, pilocarpine hydrochloride, phenylephrine hydrochloride, acetylcholine hydrochloride, pilocarpine hydrochloride, pilocarpine hydrochloride . Composition according to claim 1, characterized in that the viscoelastic polymer consists of one or more polymers selected from the group consisting of hyaluronic acid, chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratansulfate, carboxymethylhydroxyethylcellulose, cellulose sulfate, phosphate cellulose, carboxymethylguar, carboxymethylhydroxypropylguar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, alginates, furcellaran, pectins, gum arabic, tragacanth, carragenates, starch phosphates, starch succinates and copolymers, glycoaminides, glycoaminides, glycoaminides, glycoaminides, glycoaminides N-vinyl-pyrrolidone, dimethylacrylamide, acrylic acid, methacrylic acid, maleic anhydride, vinylsulfonic acid, styrene carboxylic acid, 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid and 2-methacryloyloxyethylsulfonic acid. 01-2059-99-Ce The composition of claim 5, wherein the viscoelastic polymer comprises one or more polymers selected from the group consisting of hyaluronic acid, chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxyethyl cellulose, cellulose sulfate, phosphate cellulose, carboxymethylguar, carboxymethylhydroxypropylguar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, alginates, furcellaran, pectins, gum arabic, tragacanth, carragenates, starch phosphates, starch succinates and copolymers, glycoaminides, glycoaminides, glycoaminides, glycoaminides, glycoaminides N-vinyl-pyrrolidone, dimethylacrylamide, acrylic acid, methacrylic acid, maleic anhydride, vinylsulfonic acid, styrene carboxylic acid, 2-acrylamido-2-methylpropanesulfonic acid, vinylphosphonic acid and 2-methacryloyloxyethylsulfonic acid. Composition according to claim 1, characterized in that the anesthetic agent is selected from the group consisting of lidocaine, proparacaine, tetracaine, phenacaine, naepain, cocaine, betoxycaine, bupivacaine, butacaine, butanilicaine, butoxycaine, carticaine, cyclomethycaine, dibucaine, dibucaine, dibucaine , formkain, hexylcaine, hydroxytetracaine, leucinocaine, mepivacaine, meprylcaine, metabutoxycaine, myrtekaine, octacaine, orthocaine, oxethazine, parethoxycaine, piperocaine, pyridocaine, pyrilocaine, procaine, propoxycaine, propacocaine, propacocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine . • · • · 01-2059-99-Ce 10. The composition of claim 5, wherein the anesthetic agent is selected from the group consisting of lidocaine, proparacaine, tetracaine, phenacaine, naepain, cocaine, betoxycaine, bupivacaine, butacaine, butanilicaine, butoxycaine, carticaine, cyclomethycaine, dibucaine, dibucaine, dibucaine, dibucaine. , formkain, hexylcaine, hydroxytetracaine, leucinocaine, mepivacaine, meprylcaine, metabutoxycaine, myrtekaine, octacaine, orthocaine, oxethazine, parethoxycaine, piperocaine, pyridocaine, pyrilocaine, procaine, propoxycaine, propacocaine, propacocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine, propocaocaine . 11. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is lidocaine. 12. The composition of claim 5 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is lidocaine. 13. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is tetracaine. 01-2059-99-Eng · · · · · · · · · · · · · · · · · The composition of claim 5, wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is tetracaine. 15. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is proparacaine. The composition of claim 5, wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is proparacaine. 17. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is phenacaine. The composition of claim 5, wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is fenacaine. 19. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is cocaine. • 9 9 9 9 9 9 9 9 9 9 9 01-2059-99-· ί ϊ: ϊ ’ϊ 9999 99 99 The composition of claim 5, wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is cocaine. 21. The composition of claim 1 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is naepain. 22. The composition of claim 5 wherein the viscoelastic polymer is hyaluronic acid and the anesthetic agent is naepain. 23. The composition of claim 1 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is lidocaine hydrochloride. 24. The composition of claim 5 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is lidocaine hydrochloride. 25. The composition of claim 1 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is proparacaine hydrochloride. 01-2059-99-Ce 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · · · · · · · · · · · · · · · · 9 9999 99 99 26. The composition of claim 5, wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is proparacaine hydrochloride. 27. The composition of claim 1 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is phenacaine hydrochloride. 28. The composition of claim 5 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is phenacaine hydrochloride. 29. The composition of claim 1 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is cocaine hydrochloride. 30. The composition of claim 5 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is cocaine hydrochloride. 31. The composition of claim 1 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is naepain hydrochloride. 01-2059-99-English • 9 9 9 · 9 99 99 • 99 · 9 999 9 99 9 9,999,999,999 « 99,999 9,999,999 9 32. The composition of claim 5 wherein the viscoelastic polymer is sodium hyaluronate and the anesthetic agent is naepain hydrochloride. 33. The composition of claim 5 wherein the complex is selected from the group consisting of atropine-lidocaine-hyaluronate, atropine-proparacaine-hyaluronate, atropine-tetracaine-hyaluronate, atropine-phenacaine-hyaluronate, atropine-cocaine-hyaluronate, atropaluronate. atropine-lidocaine-chondroitin sulfate, atropine-proparacaine-chondroitin sulfate, atropine-tetracaine-chondroitin sulfate, atropine-phenacaine-chondroitin sulfate, and atropine-naepain-chondroitin sulfate. 34. The composition of claim 5 wherein the complex is selected from the group consisting of acetylcholine-lidocaine-hyaluronate, acetylcholine-proparacaine-hyaluronate, acetylcholine-tetracaine-hyaluronate, acetylcholine-phenacaine-hyaluronate, acetylcholine-cocaine-hyaluronate, naepain-hyaluronate, acetylcholine-lidokaine-chondroitin sulfate, acetylcholine-proparacaine-chondroitin sulfate, acetylcholine-tetracaine-chondroitin sulfate, acetylcholine-phenacaine-chondroitin sulfate, and acetylcholine-naepain-chondroitin sulfate. 01-2059-99-Če • · · · φ · · · · · · · · · · • · • · • · • · • · • · • · • · φ · φ · · · · · · · · · 35. The composition of claim 5, wherein the complex is selected from the group consisting of pilocarpine-lidocaine-hyaluronate, pilocarpine-proparacaine-hyaluronate, pilocarpine-tetracaine-hyaluronate, pilocarpine-enaine-hyaluronate, pilocarpine-cocaine-hyaluronate, naocine-hyaluronate, pilocarpine-lidocaine-chondroitin sulfate, pilocarpine-proparacaine-chondroitin sulfate, pilocarpine-tetracaine-chondroitin sulfate, pilocarpine-phenacaine-chondroitin sulfate and pilocarpine-naepain-chondroitin sulfate. 36. A method of maintaining structural integrity of the anterior chamber during surgery while providing anesthesia, comprising administering to the subject a viscoelastic polymer and a therapeutically effective amount of the anesthetic agent.